Lumichrome Inhibits Human Lung Cancer Cell Growth and Induces Apoptosis via a p53-Dependent Mechanism.

Lumichrome, a major derivative of riboflavin, may exhibit pharmacological activity against cancer cells. Riboflavin is a vitamin found in food, however, certain evidence has suggested its possible potentiating effects on cancer progression. Here, we have shown for the first time that unlike riboflavin, lumichrome can suppress lung cancer cell growth and reduce survival in both normal and anchorage-independent conditions. In addition, lumichrome induced apoptosis in lung cancer cells via a p53-dependent mitochondrial mechanism with substantial selectivity, shown by its lesser toxicity to the normal primary dermal papilla cells. The potency of lumichrome in killing lung cancer cells was found to be comparable to that of cisplatin, a standard chemotherapeutic drug for lung cancer treatment. With regard to the mechanism, lumichrome significantly upregulated p53 and decreased its downstream target BCL-2. Such a shift of BCL-2 family protein balance further activated caspase-9 and -3 and finally executed apoptosis. Furthermore, lumichrome potentially suppressed cancer stem cells (CSCs) in lung cancer by dramatically suppressing CSC markers together with the CSC-maintaining cell signaling namely protein kinase B (AKT) and ß-catenin. To conclude, the present study has unraveled a novel role and mechanism of lumichrome against lung cancer that may benefit the development of the compound for management of the disease.

5-O-Acetyl-Renieramycin T from Blue Sponge Xestospongia sp. Induces Lung Cancer Stem Cell Apoptosis.

Lung cancer is one of the most significant cancers as it accounts for almost 1 in 5 cancer deaths worldwide, with an increasing incident rate. Management of the cancer has been shown to frequently fail due to the ability of the cancer cells to resist therapy as well as metastasis. Recent evidence has suggested that the poor response to the current treatment drugs and the ability to undergo metastasis are driven by cancer stem cells (CSCs) within the tumor. The discovery of novel compounds able to suppress CSCs and sensitize the chemotherapeutic response could be beneficial to the improvement of clinical outcomes. Herein, we report for the first time that 5-O-acetyl-renieramycin T isolated from the blue sponge Xestospongia sp. mediated lung cancer cell death via the induction of p53-dependent apoptosis. Importantly, 5-O-acetyl-renieramycin T induced the death of CSCs as represented by the CSC markers CD44 and CD133, while the stem cell transcription factor Nanog was also found to be dramatically decreased in 5-O-acetyl-renieramycin T-treated cells. We also found that such a CSC suppression was due to the ability of the compound to deplete the protein kinase B (AKT) signal. Furthermore, 5-O-acetyl-renieramycin T was able to significantly sensitize cisplatin-mediated apoptosis in the lung cancer cells. Together, the present research findings indicate that this promising compound from the marine sponge is a potential candidate for anti-cancer approaches.

Ti0.8O2 Nanosheets Inhibit Lung Cancer Stem Cells by Inducing Production of Superoxide Anion.

Recent research into the cancer stem cell (CSC) concept has driven progress in the understanding of cancer biology and has revealed promising CSC-specific targets for drug discovery efforts. As malignancies of lung cancer have been shown to be strongly associated with activities of CSCs, we examined the effects of Ti0.8O2 nanosheets on these cells. Here we show that the nanosheets target lung CSCs but not normal primary dermal papilla (DP) stem cells. Whereas Ti0.8O2 caused a dramatic apoptosis along with a decrease in CSC phenotypes, in primary human DP cells such effects of nanosheets have been minimal. Nanosheets reduced the ability of lung cancer cells to generate three-dimensional tumor spheroids, lung CSC markers (CD133 and ALDH1A1), and CSC transcription factors (Nanog and Oct-4). Ti0.8O2 nanosheets reduced CSC signaling through mechanisms involving suppression of protein kinase B (AKT) and Notch-1 pathways. In addition, the nanosheets inhibited the migration and invasive activities of lung cancer cells and reduced epithelial-to-mesenchymal transition (EMT) markers as N-cadherin, vimentin, and Slug, as well as metastasis-related integrins (integrin-αv and integrin-ß1). Importantly, we found that the selectivity of the Ti0.8O2 nanosheets in targeting cancer cells was mediated by induction of cellular superoxide anion in cancerous but not normal cells. Inhibition of nanosheet-induced superoxide anion restored the suppression of CSC and EMT in cancer cells. These findings demonstrate a promising distinctive effect of Ti0.8O2 nanosheets on lung CSC that may lead to opportunities to use such a nanomaterial in cancer therapy.

Lung Cancer Stem Cells and Cancer Stem Cell-targeting Natural Compounds.

The novel information regarding molecular and translational research have created a paradigm shift in the understanding of lung cancer biology, revealing the more precise target for anti-cancer drug discovery. Lung cancer is a leading cause of cancer death worldwide accounting for approximately 1 in 5 of all cancer-related deaths. The most important causes of death in such a cancer involves the treatment failure as well as the spreading of cancer cells to distant sites which the cancer stem cell (CSC) within the tumor is accepted as a key driver. CSC is a rare special population of cancer cells exhibiting high tumorigenic properties together with self-renewal and differentiation capability. CSC is not only linked with high tumor-initiating activity, but is also implicated in chemotherapeutic resistance, metastasis, epithelial to mesenchymal transition, and recurrence. Thereafter, novel therapeutic strategies targeting these CSCs are considered in order to improve long-term clinical outcome. Here, we provide sufficient data regarding the biology of CSC in lung cancer, known CSC markers and cellular signals, and promising compounds targeting the stem cell signals in lung cancer that may benefit the development of novel anti-cancer treatment.

Microphthalmia-associated transcription factor as the molecular target of cadmium toxicity in human melanocytes.

Dietary intake of cadmium is inevitable, causing age-related increase in cadmium accumulation in many organs, including hair, choroid and retinal pigment epithelium (RPE). Cadmium has been implicated in the pathogenesis of hearing loss and macular degeneration. The functions of cochlea and retina are maintained by melanocytes and RPE, respectively, and the differentiation of these pigment cells is regulated by microphthalmia-associated transcription factor (MITF). In the present study, we explored the potential toxicity of cadmium in the cochlea and retina by using cultured human melanocytes and human RPE cell lines. MITF consists of multiple isoforms, including melanocyte-specific MITF-M and widely expressed MITF-H. Levels of MITF-M protein and its mRNA in human epidermal melanocytes and HMV-II melanoma cells were decreased significantly by cadmium. In parallel with the MITF reduction, mRNA levels of tyrosinase, the key enzyme of melanin biosynthesis that is regulated by MITF-M, were also decreased. In RPE cells, however, the levels of total MITF protein, constituting mainly MITF-H, were not decreased by cadmium. We thus identify MITF-M as the molecular target of cadmium toxicity in melanocytes, thereby accounting for the increased risk of disability from melanocyte malfunction, such as hearing and vision loss among people with elevated cadmium exposure.